Global patterns of syphilis, gonococcal infection, typhoid fever, paratyphoid fever, diphtheria, pertussis, tetanus, and leprosy from 1990 to 2021: findings from the Global Burden of Disease Study 2021

Background Certain infectious diseases are caused by specific bacterial pathogens, including syphilis, gonorrhea, typhoid and paratyphoid fever, diphtheria, pertussis, tetanus, leprosy, and tuberculosis. These diseases significantly impact global health, contributing heavily to the disease burden. The study aims to thoroughly evaluate the global burden of syphilis, gonorrhea, typhoid and paratyphoid fever, diphtheria, pertussis, tetanus, and leprosy. Methods Leveraging the Global Burden of Disease (GBD) study 2021, age-specific and Socio-demographic Index (SDI)-specific incidence, disability-adjusted life-years (DALYs), and death for eight specific bacterial infections across 204 countries and territories from 1990 to 2021 were analyzed. Percentage changes in age-standardized incidence rate (ASIR), DALY rate, and mortality rate (ASMR) were also examined, with a focus on disease distribution across different regions, age groups, genders, and SDI. Results By 2021, among the eight diseases, gonococcal infection had the highest global ASIR [1096.58 per 100,000 population, 95% uncertainty interval (UI): 838.70, 1385.47 per 100,000 population], and syphilis had the highest global age-standardized DALY rate (107.13 per 100,000 population, 95% UI: 41.77, 212.12 per 100,000 population). Except for syphilis and gonococcal infection, the age-standardized DALY rate of the remaining diseases decreased by at least 55% compared to 1990, with tetanus showing the largest decrease by at least 90%. Globally, significant declines in the ASIR, age-standardized DALY rate, and ASMR for these eight bacterial infections have been observed in association with increases in the SDI. Regions with lower SDI, such as sub-Saharan Africa, experienced a relatively higher burden of these eight bacterial infections. Conclusions Although there has been an overall decline in these eight diseases, they continue to pose significant public health challenges, particularly in low SDI regions. To further reduce this burden in these areas, targeted intervention strategies are essential, including multi-sectoral collaboration, policy support, improved WASH management, and enhanced research efforts. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s40249-024-01231-2.


Background
Bacterial pathogens serve as significant contributors to the occurrence of infectious diseases.Some diseases, such as meningitis, can be caused by multiple pathogens including Streptococcus pneumoniae, Neisseria meningitidis, and even viruses [1,2].However, it is noteworthy that certain infectious diseases are attributed to specific bacterial pathogens.These include syphilis, gonorrhea, typhoid and paratyphoid fevers, diphtheria, pertussis, tetanus, leprosy, and tuberculosis (TB).
Numerous studies have convincingly demonstrated that these nine specific diseases exert a profound impact on the global burden of disease [3][4][5][6][7].Specifically, sexually transmitted infections (STIs) such as syphilis and gonorrhea, caused by Treponema pallidum and Neisseria gonorrhoeae respectively, can lead to infertility, genital damage, and an increased risk of human immunodeficiency virus (HIV) infection [8,9].Typhoid and paratyphoid fever, diseases of the intestinal system, are caused by Salmonella enterica subspecies serovars Typhi and Paratyphi [10].The global burden of typhoid fever is estimated to be about 21.7 million cases and 217,000 fatalities annually [11].Leprosy, a neglected tropical disease, is caused by the Mycobacterium leprae [12].Fortunately, the global incidence of leprosy has decreased by 27.86% from 1990 to 2019 following the implementation of multidrug therapy by the World Health Organization (WHO) [5,13].Diphtheria, pertussis, and tetanus are caused by Corynebacterium diphtheriae, Bordetella pertussis, and Clostridium tetani, respectively.Despite the effectiveness of the diphtheria-tetanus-pertussis (DTP) vaccine in preventing and controlling these diseases, complete elimination remains unattainable at present [14].Tuberculosis, caused by Mycobacterium tuberculosis, stands as a formidable global health issue, responsible for a considerable number of deaths, ranking second only to coronavirus disease 2019  in terms of mortality rates [15].The WHO has implemented corresponding measures to combat these nine diseases, including strategies to end STIs, TB, and leprosy, as well as efforts to strengthen vaccine coverage, including the DTP, typhoid, and paratyphoid vaccines [16][17][18][19][20][21].
The Global Burden of Disease (GBD) 2021 database is designed to assess the global burden of 371 diseases in 204 countries and territories from 1990 to 2021 [22].According to the GBD study 2021, estimates of the disease burden for TB in 2021 have been thoroughly investigated [7].It is also necessary to estimate the disease burden of eight other specific bacterial infections by country, region, age, sex, and SDI, particularly to provide information on the prevalence during the COVID-19 pandemic (after 2019).In this study, the results of GBD 2021 were utilized to estimate the burden of these eight specific bacterial pathogens, analyzing epidemiological data to determine transmission trends at global and regional levels.

Statistical analysis
Age-standardized rate (ASR) per 100,000 population were extracted from the GBD 2021 database, including age-standardized incidence rate (ASIR), age-standardized DALY rate, and age-standardized mortality rate (ASMR).The ASR is calculated based on the age structure of standard populations using the following formula: where a i is the age-specific rate in the i th age group, w i is the number of persons (or the weight) in the corresponding i th age subgroup of the selected reference standard population, and N is the number of age groups.The 95% uncertainty intervals (UIs) were defined as the 2.5th and 97.5th values of the ordered 1000 draws.
The GBD database utilizes UIs rather than precise statistical values.Therefore, in this study, statistical significance cannot be directly calculated when comparing two numerical values, like numbers and rates; only UIs are provided.If the UIs overlap, it suggests no significant difference (P > 0.05).On the other hand, if the UIs do not overlap, it indicates a significant difference (P < 0.05).
Smoothing spline models were used to evaluate the relationship between the burdens of the eight diseases and SDI across the 21 geographic regions and 204 countries and territories.The expected values were determined through calculations that consider the SDI and disease rates across all locations.Smooth splines were applied using the ggplot2 with geom_smooth by method "loess" [23].

Global distribution of eight bacterial diseases Syphilis
For syphilis in 2021, the ASIR was highest in Central sub-Saharan Africa, followed by Eastern sub-Saharan Africa and Southern sub-Saharan Africa, exceeding 460.00 per 100,000 population (Table 1).The countries with the highest ASMR for syphilis are Equatorial Guinea, Central African Republic, and the Democratic Republic of the Congo.In contrast, the regions with an ASIR below 100.00 per 100,000 population include Central Europe, Central Asia, and Western Europe (Table 1), among which the top three lowest ASIR countries were Bulgaria, Slovakia, and Croatia.The age-standardized DALY rate had a similar geographical distribution, being highest in Central, Eastern and Southern sub-Saharan Africa, greater than 100.00 per 100,000 population (Table 1), and South Sudan, the Central Africa Republic, and Liberia had the dominant DALY rates.In contrast, the age-standardized DALY rate was lowest in high-income North America and Australasia, both below 1.00 per 100,000 population (Additional file 1: Table S9).

Gonococcal infection
Gonococcal infection had the highest ASIR in Southern sub-Saharan Africa, followed by Oceania and Central Europe in 2021, exceeding 2170.00 per 100,000 population (Table 2).South Africa, Papua New Guinea and Lesotho were three countries with the highest ASIR.Age-standardized DALY rate was highest in Eastern sub-Saharan Africa, and Central sub-Saharan Africa (Table 2).Somalia, Lesotho, and South Africa were the three agestandardized highest DALY rate countries for gonococcal infection (Additional file 1: Table S9).

Typhoid fever
The ASIR of typhoid fever was highest in Oceania, South Asia, and Southeast Asia in 2021, exceeding 142.00 per 100,000 population (Table 3).The age-standardized DALY rate and ASMR had the same trends, which are also dominant in these three regions (Table 3 and Additional file 1: Table S3).Burkina Faso, Bangladesh, and Papua New Guinea were the three most dominant countries with disease incidence burden, compared to Belgium, Croatia and Canada, which were the three least dominant countries (Additional file 1: Table S9).

Paratyphoid fever
Oceania and South Asia had the highest ASIR, age-standardized DALY rate and ASMR for paratyphoid fever in 2021, exceeding 112.00 per 100,000 population, 25.00 per 100,000 population and 0.34 per 100,000 population, respectively (Table 4 and Additional file 1: Table S4).For paratyphoid fever, India, Pakistan, and Nepal had the highest ASIR, DALY rate and ASMR (Additional file 1: Table S9).

Diphtheria
Diphtheria had the most dominant ASIR in Oceania in 2021, up to 1.15 per 100,000 population (Table 5), but African areas, including Somalia, Central Africa Republic, and Nigeria were the top three ASIR countries.The most dominant age-standardized DALY rate was in Western sub-Saharan Africa, exceeding 215.00 per 100,000 population (Table 5 and Additional file 1: Table S9).

Pertussis
For pertussis, the top region of ASIR, age-standardized DALY rate and ASMR was Central sub-Saharan Africa, exceeding 475.00 per 100,000 population, 323.00 per 100,000 population and 3.72 per 100,000 population, respectively in 2021 (Table 6 and Additional file 1: Table S6).Among these regions, Angola, Central African Republic, and Somalia had the highest ASIR (Additional file 1: Table S9).

Tetanus
Tetanus had the highest ASIR, age-standardized DALY rate and ASMR in Eastern sub-Saharan Africa in 2021, exceeding 3.31 per 100,000 population, 96.46 per 100,000 population and 1.94 per 100,000 population respectively (Table 7 and Additional file 1: Table S7).Somalia and South Sudan were the two countries with the dominant ASIR and age-standardized DALY rate (Additional file 1: Table S9).

Leprosy
Leprosy was the most prevalent in Tropical Latin America, with the highest ASIR and age-standardized DALY rate compared to other regions (Table 8).Micronesia, Kiribati, and Marshall Islands had the highest incidence rate, and Kiribati, Tuvalu and Micronesia had the highest DALY rate.There were no death-related data reported for this disease (Additional file 1: Table S9).

Gender and age distribution for eight bacterial diseases
For syphilis, in the 50-54 age group, the specific incidence rate is higher in males than in females (P < 0.05), with no significant differences observed in other age groups (P > 0.05, equally).For leprosy, the specific incidence rate between males and females shows no significant difference in the 20-24 and 50-54 age groups (P > 0.05, equally), while in other age groups, males have a significantly higher incidence rate than females (P < 0.05).The specific incidence rates for gonococcal infection, typhoid and paratyphoid fever, diphtheria, pertussis, and tetanus show no differences between males and females across all age groups (P > 0.05, equally, Fig. 1A-H).
In the 45-54, 60-64 age groups and above, the specific DALY rates for syphilis are higher in males than in females (P < 0.05), with no significant differences in other age groups (P > 0.05, equally).In the 10-24 and 50-54 age groups the specific DALY rates for gonococcal infection are higher in males than in females (P < 0.05), with no significant differences in other age groups (P > 0.05, equally).For leprosy, only in the > 95 age group, the specific incidence rate is higher in males than in females (P < 0.05), with no significant differences observed in other age groups (P > 0.05, equally).The specific DALY rate for other five diseases show no differences between males and females across all age groups (P > 0.05, equally, Additional file 2: Fig. S1A-H).
In the 45-49, 75-79, 85-89, and > 95 age groups, the specific mortality rate of syphilis is higher in males than in females (P < 0.05), with no significant differences in other age groups (P > 0.05, equally).The specific mortality rates for other diseases show no differences between   Incidence rate per 100,000 population of syphilis Fig. 2 Age-standardized incidence rates per 100,000 population of Syphilis (A), Gonococcal infection (B), Typhoid fever (C), Paratyphoid fever (D), Diphtheria (E), Pertussis (F), Tetanus (G) and Leprosy (H) from 1990 to 2021 by five SDI regions.SDI Socio-demographic Index males and females across all age groups (P > 0.05, equally, Additional file 2: Fig. S2A-G).
The specific DALY rate is highest in the < 5 age group for syphilis, typhoid, paratyphoid, diphtheria, pertussis, and tetanus.The specific incidence rate is highest in the < 5 age group for typhoid, paratyphoid, diphtheria, pertussis, and tetanus (Fig. 1A-H and Additional file 2: Fig. S1A-H).
In 2021, ASIR of syphilis and pertussis showed a sharp decline with SDI increased, and typhoid fever and paratyphoid fever, diphtheria, tetanus, and leprosy had a slight decreasing trend with increasing SDI.ASIR of gonococcal infection kept stable first and then decreased with increasing SDI (Additional file 2: Fig. S5).There was a sharp decrease with rising SDI for age-standardized DALY rate in syphilis, gonococcal infection, pertussis, and leprosy, whereas there was a slight decrease for typhoid fever, paratyphoid fever, diphtheria, and tetanus (Additional file 2: Fig. S6).The ASMR of syphilis, gonococcal infection, and pertussis had a steeply inverse relationship with SDI, whereas typhoid fever, paratyphoid fever, diphtheria, and tetanus had a slightly negative correlation with SDI (Additional file 2: Fig. S7).
From 1990 to 2021, the ASIR, age-standardized DALY rate and ASMR for syphilis, diphtheria, pertussis, and tetanus declined rapidly with increases in SDI in 21 GBD regions globally (Additional file 2: Fig. S8

Variance analysis in 21 geographic regions of the globe
In 2021, globally, among the eight bacterial infections, the top three diseases with the highest ASIR were gonorrhea, syphilis, and pertussis; the top three diseases with the highest age-standardized DALY rate were syphilis, typhoid, and pertussis; and the top three diseases with the highest ASMR were typhoid, syphilis, and pertussis (Fig. 3A-C).The ASIR of typhoid fever was notably higher in South Asia compared to other GBD regions.Typhoid and paratyphoid fever showed relatively higher DALY rates in South Asia and Oceania.(Fig. 3A-B).

Discussion
This study provides a comprehensive estimation of the global incidence, DALYs, and death of eight bacterial diseases.In 2021, except for the two STIs, syphilis and gonococcal infections, the age-standardized DALY rates for all other diseases declined by at least 55% compared to 1990.Compared to 2019, when the COVID-19 pandemic began, the global ASIR and age-standardized DALY rate of syphilis increased in 2021, gonococcal infection rates remained stable, and the other infectious diseases' rates decreased, with pertussis showing a particularly steep reduction.Regions with higher SDI experienced a lower burden of these eight diseases, whereas low SDI regions continue to require considerable attention for future prevention and control efforts.

Diphtheria, pertussis and tetanus
The ASIR and age-standardized DALY rate for diphtheria, pertussis, and tetanus saw a notable reduction, owing to the widespread adoption of the DTP vaccine [24].These diseases exhibited a notably higher age-standardized DALY rate among children under 5 years old, especially in regions with a comparatively low SDI such as sub-Saharan African areas.In such areas, healthcare systems are relatively underdeveloped, and opportunities for bacteria transmission are higher [25].Additionally, the DTP vaccine requires three doses to produce protective antibodies, and complete vaccination has not been achieved in these areas [26,27].Therefore, to better control these three infections, DTP vaccine penetration in the impoverished areas needs to be strengthened.Notably, there was a steep decrease in pertussis cases between 2019 and 2021, possibly owing to the protective effects of COVID-19 quarantine measures.The related measures including social isolation, wearing masks, maintaining hand hygiene, and limiting public gatherings, have effectively mitigated the spread of not only SARS-CoV-2 but also other respiratory infections, including pertussis [28].

Syphilis and gonococcal infection
While high SDI areas have better prevention and control measures for STIs compared to low SDI areas, syphilis, and gonococcal infection remain problematic even in high SDI regions.The higher age-standardized DALY rates for gonococcal infection may be attributed to some youth having multiple and occasional sexual partners, as well as the increasing resistance of Neisseria gonorrhoeae to many commonly used antibiotics, which complicates treatment [29,30].Syphilis contributes to increased agestandardized DALY rates in newborns, primarily due to congenital syphilis, which is transmitted from infected mothers to their fetuses, causing serious health problems and a substantial mortality rate [31].Since 2020, the ASIR and age-standardized DALY rates of syphilis have increased in many regions, which is likely due to the redirection of medical attention towards the COVID-19 pandemic, impeding access to testing and treatment for pregnant women [32,33].

Typhoid and paratyphoid fevers
South Asia continues to be a significant epicenter for typhoid fever, as was the case in 2021 GBD study [34].Despite a continued decline in ASIR of typhoid and paratyphoid fevers in South Asia, the disease burden remains considerable.Water, sanitation, and hygiene (WASH) are critically important in controlling enteric fever, but improving these aspects is usually a long process.In the short term, reducing the disease burden of typhoid and paratyphoid fevers in South Asia requires immunization coverage.Some countries have already started immunization programs for typhoid fever, but eliminating typhoid fever transmission in the region requires more countries to implement vaccination strategies [35,36].

Leprosy
Leprosy, classified as a neglected tropical disease, exhibits the lowest disease burden among the range of bacterial infections under study.However, it has great damage to peripheral nerves, resulting in loss of sensation, resulting in skin damage and disability [37].Leprosy-related deaths are mainly due to complications and chronic conditions associated with the disease [38].Tropical areas, such as tropical Latin America, have relatively higher leprosy ASIR and age-standardized DALY rates.Vaccination has proven effective in preventing and controlling leprosy before it manifests [39].The male group exhibited a higher DALY rate than females, which is probably due to greater exposure of men to the Mycobacterium leprae bacillus or the lack of full medical examinations for women in some cultures [40].
One Health is an increasingly prominent approach that emphasizes the interconnectedness of human, animal, and environmental health.This holistic strategy acknowledges that human death is closely linked to the health of animals and our shared environment.As global challenges such as antimicrobial resistance, zoonotic diseases, and climate change intensify, the One Health approach has gained significant attention and importance [41].To address the ongoing threat of bacterial infectious diseases, a One Health strategy that integrates robust policy support, multi-sectoral collaboration, animal health monitoring, environmental management, and enhanced research is crucial for effective and comprehensive bacterial infection control [42].For typhoid and paratyphoid fever, prevention involves improving WASH alongside effective vaccination campaigns.Environmental management is essential to reduce contamination sources, while public health education raises awareness about hygiene practices [43].Evidence suggests that armadillos can harbor the Mycobacterium leprae that cause leprosy [44].Monitoring and managing these animal reservoirs, along with studying the One Health microbiome across humans, animals, and the environment, are crucial to prevent zoonotic transmission and control the disease [45].
This study has several limitations.First, significant variations in the quality and availability of data from GBD databases can occur across different regions and countries.In many low-and middle-income countries, limited health data and incomplete reporting can lead to uncertainties in the estimates.Second, while useful, the SDI may not fully capture the complex interplay of social, economic, and environmental factors influencing disease burden.Finally, because GBD 2021 data are model-based rather than derived from real-world data, they may lead to potential overestimation or underestimation.

Conclusions
This study utilized current data from the GBD 2021 to estimate the disease burdens of syphilis, gonococcal infection, typhoid and paratyphoid fever, diphtheria, pertussis, tetanus, and leprosy.Despite an overall decline in eight diseases, it remains a significant challenge to global public health, especially in low SDI areas.To further alleviate burden of disease on society, proactive intervention strategies at governmental and medical levels should be implemented based on the geographical and epidemiological distribution, including multi-sectoral collaboration, policy support, WASH management, and enhanced research.

Fig. 3
Fig. 3 Heatmap of eight specific bacterial infections in 21 GBD regions in 2021.Age-standardized incidence rate (A), age-standardized DALY rate (B), and age-standardized mortality rate per 100,000 population (C).DALY: disability-adjusted life year, GBD Global Burden of Disease

Table 1
(continued)DALY disability-adjusted life year, GBD Global Burden of Disease, SDI Socio-demographic Index, UI uncertainty interval

Table 2
Age-standardized incidence and DALY rates for gonococcal infection in 1990 and 2021, and the percentage change in the age-standardized rates per 100,000 population by GBD region, from 1990 to 2021

Table 3
Age-standardized incidence and DALY rates for typhoid fever in 1990 and 2021, and the percentage change in the agestandardized rates per 100,000 population by GBD region, from 1990 to 2021

Table 3
(continued)DALY disability-adjusted life year, GBD Global Burden of Disease, SDI Socio-demographic Index, UI uncertainty interval

Table 4
Age-standardized incidence and DALY rates for paratyphoid fever in 1990 and 2021, and the percentage change in the agestandardized rates per 100,000 population by GBD region, from 1990 to 2021

Table 4 (
continued) DALY disability-adjusted life year, GBD Global Burden of Disease, SDI Socio-demographic Index, UI uncertainty interval

Table 5
Age-standardized incidence and DALY rates for diphtheria in 1990 and 2021, and the percentage change in the agestandardized rates per 100,000 population by GBD region, from 1990 to 2021

Table 5
(continued)DALY disability-adjusted life year, GBD Global Burden of Disease, SDI Socio-demographic Index, UI uncertainty interval

Table 6
Age-standardized incidence and DALY rates for pertussis in 1990 and 2021, and the percentage change in the agestandardized rates per 100,000 population by GBD region, from 1990 to 2021

Table 6
(continued)DALY disability-adjusted life year, GBD Global Burden of Disease, SDI Socio-demographic Index, UI uncertainty interval

Table 7
Age-standardized incidence and DALY rates for tetanus in 1990 and 2021, and the percentage change in the agestandardized rates per 100,000 population by GBD region, from 1990 to 2021

Table 7
(continued) DALY disability-adjusted life year, GBD Global Burden of Disease, SDI Socio-demographic Index, UI uncertainty interval , AEFG & S9, AEFG & S10, AEFG).However, these trends varied across different GBD regions.The ASIR, ASMR and age-standardized DALY rate for syphilis increased and then decreased with rising SDI in Central sub Saharan Africa, whereas was stable in North Africa and Middle East, Central Europe, high-income Asia Pacific, and Eastern Europe (Additional file 2: Figs.S8A, S9A and S10A).The ASIR of gonococcal infection was relatively stable in all GBD regions except for Southern sub-Saharan Africa and Oceania (increased and then decreased with increasing SDI).By contrast, age-standardized DALY rate and ASMR of gonococcal infection decreased globally with rising SDI (Additional file 2: Fig. S8B, S9B and S10B).